rs397516363

Variant names:

• chr15-63044075-G-A
• rs397516363
• NM_001018005.2:c.163G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-63044075-G-A
• chr15-63044075-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_001018005.2(TPM1):​c.163G>A​(p.Asp55Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D55G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.56
• Publications: 1 publications found

Genes affected

TPM1 (HGNC:12010): (tropomyosin 1) This gene is a member of the tropomyosin family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosin is composed of two alpha-helical chains arranged as a coiled-coil. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. The encoded protein is one type of alpha helical chain that forms the predominant tropomyosin of striated muscle, where it also functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. In smooth muscle and non-muscle cells, alternatively spliced transcript variants encoding a range of isoforms have been described. Mutations in this gene are associated with type 3 familial hypertrophic cardiomyopathy and dilated cardiomyopathy 1Y. [provided by RefSeq, Jun 2022]

TPM1-AS (HGNC:53635): (TPM1 antisense RNA)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 18 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-63044075-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 691666.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 15-63044075-G-A is Pathogenic according to our data. Variant chr15-63044075-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43404.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.163G>A	p.Asp55Asn	missense_variant	Exon 2 of 10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.163G>A	p.Asp55Asn	missense_variant	Exon 2 of 10	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

Apr 20, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Asp55Asn variant has not been reported in the literature nor been previously identified by our laboratory. Aspartic acid (Asp) at amino acid position 55 is highly conserved across evolutionary distant species, increasing the likelihood that the change is pathogenic. In addition, this family?s racial origin is repor ted to be Caucasian and the Asp55Asn variant has not been identified in over 165 0 Caucasian probands tested by our laboratory (LMM unpublished data). This low f requency also supports a pathogenic role. Finally, this variant was predicted to be pathogenic using a novel computational tool, which was validated by our labo ratory using a set of cardiomyopathy variants with well-established clinical sig nificance. This tool's pathogenic prediction is estimated to be correct 94% of t he time, which suggests but does not prove that this variant is pathogenic (Jord an 2011). In summary, this variant is likely to be pathogenic. -

Dilated cardiomyopathy 1Y Uncertain:1

Aug 25, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.90 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change(ClinVar ID: VCV000043404) and a different missense change at the same codon (p.Asp55Tyr / ClinVar ID: VCV000691666) have been previously reported to be associated with TPM1 related disorder. However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
CardioboostCm	Uncertain	0.35
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;.;T;.;D;D;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.7	L;L;.;.;L;.;L;.
PhyloP100		9.6
PROVEAN	Benign	-1.9	N;N;.;N;N;N;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.20	T;D;.;T;T;D;D;.
Sift4G	Benign	0.55	T;T;T;T;T;T;T;.
Polyphen		0.33, 0.97	.;.;.;.;B;D;.;.
Vest4		0.70
MutPred		0.58		.;.;.;.;.;Loss of phosphorylation at T95 (P = 0.1089);.;.;
MVP		0.88
MPC		2.4
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.43
gMVP		0.91
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516363; hg19: chr15-63336274;